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miR-150-PTPMT1-cardiolipin signaling in pulmonary arterial hypertension

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Title: miR-150-PTPMT1-cardiolipin signaling in pulmonary arterial hypertension
Authors: Russomanno, G
Jo, KB
Abdul-Salam, V
Morgan, C
Endruschat, J
Schaeper, U
Osman, A
Alzaydi, M
Wilkins, M
Wojciak-Stothard, B
Item Type: Journal Article
Abstract: Circulating levels of endothelial miR-150 are reduced in pulmonary arterial hypertension (PAH) and act as an independent predictor of patient survival, but links between endothelial miR-150 and vascular dysfunction are not well understood. We studied the effects of endothelial miR-150 supplementation and inhibition in PAH mice and cells from patients with idiopathic PAH. The role of selected mediators of miR-150 identified by RNA sequencing was evaluated in vitro and in vivo. Endothelium-targeted miR-150 delivery prevented the disease in Sugen/hypoxia mice, while endothelial knockdown of miR-150 had adverse effects. miR-150 target genes revealed significant associations with PAH pathways, including proliferation, inflammation, and phospholipid signaling, with PTEN-like mitochondrial phosphatase (PTPMT1) most markedly altered. PTPMT1 reduced inflammation and apoptosis and improved mitochondrial function in human pulmonary endothelial cells and blood-derived endothelial colony-forming cells from idiopathic PAH. Beneficial effects of miR-150 in vitro and in vivo were linked with PTPMT1-dependent biosynthesis of mitochondrial phospholipid cardiolipin and reduced expression of pro-apoptotic, pro-inflammatory, and pro-fibrotic genes, including c-MYB, NOTCH3, transforming growth factor β (TGF-β), and Col1a1. In conclusion, we are the first to show that miR-150 supplementation attenuates pulmonary endothelial damage induced by vascular stresses and may be considered as a potential therapeutic strategy in PAH.
Issue Date: 1-Mar-2021
Date of Acceptance: 28-Oct-2020
URI: http://hdl.handle.net/10044/1/85107
DOI: 10.1016/j.omtn.2020.10.042
ISSN: 2162-2531
Publisher: Nature Publishing Group
Start Page: 142
End Page: 153
Journal / Book Title: Molecular Therapy : Nucleic Acids
Volume: 23
Copyright Statement: © 2020 The Author(s).This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
Sponsor/Funder: British Heart Foundation
Royal Embassy Of Saudi Arabia
Funder's Grant Number: PG/16/4/31849
Keywords: 0601 Biochemistry and Cell Biology
1103 Clinical Sciences
Publication Status: Published
Online Publication Date: 2020-11-04
Appears in Collections:National Heart and Lung Institute

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